It is well known that placental function has a major impact on fetal growth and development and thus on reproductive efficiency and health. Recent studies, including those in gene-knockout mice, indicate that vascular endothelial growth factors (VEGF), fibroblast growth factors (FGF), and angiopoietins (ANG) play major roles in the development and organization of the placental vasculature. The Long-term Goal of this proposal is to determine the role of these major angiogenic growth factors in placental angiogenesis during normal and compromised pregnancies. In Specific Aim 1, we will test Hypothesis l: that major angiogenic factors, namely VEGF, basic FGF (bFGF or FGF 2), and -ANG1, and their receptors, are expressed in a time- and cell-specific fashion throughout gestation. In this study, we also will correlate placental vascular development with the pattern of expression of these major angiogenic factors and their receptors in normal pregnancies. In Specific Aim 2, we will test Hypothesis 2: that placental size is determined by the fetal genome but that placental vascularity depends primarily on the maternal genome (the "uterine environment"); additionally we hypothesize that differences in placental vascularity can be explained by changes in placental expression of VEGF, bFGF, ANG1, and(or) their receptors. For this study, we will use a model that we have recently established for reciprocal embryo transfer between a highly prolific and a less prolific breed of sheep. In Specific Aims 3 and 4, we will test Hypotheses 3 and 4: that decreased placental and fetal size resulting ' from maternal undernutrition (Specific Aim 3) or maternal age at first pregnancy (Specific Aim 4) can be explained by reduced placental expression of the major angiogenic factors and(or) their receptors resulting in reduced placental vascular development. The proposed studies wilt provide a solid foundation for future studies and, in addition, address important issues in pregnancy research; namely, the effects of the fetal and maternal genomes, maternal undernutrition, and maternal age, respectively, on placental vascular development.